Composition and a method for relieving broncho-spasms which use 1-p-hydroxyphenyl - 2 - (beta - 3&#39;,5&#39; - dihydroxyphenyl - beta-hydroxy)-ethylaminopropane



United States Patent M 3 Claims. (cl. 424-45 ABSTRACT OF THE DISCLOSUREThe composition contains a l-p-hydroxyphenyl-Z-(fl-3',5'-dihydroxyphenyl- 8 hydroxy) ethylamino-propane as an activebroncho-spasmolytic ingredient.

This is a division of copending application Ser. No. 326,398, filed Nov.27, 1963, now U.S. Patent 3,341,593 issued Sept. 12, 1967.

This invention relates to a novel broncho-spasmolytic composition, aswell as to a novel method of treating broncho-spasms in warm-bloodedanimals.

More particularly, the present invention relates to a pharmaceuticalcomposition comprising as an active ingredient a racemic mixture of thecompound of the formula HO OH an optical antipode thereof, astereoisomer thereof, or a non-toxic, pharmacologically acceptable acidaddition salt of said racemic mixture, optical antipode or stereoisomer.

The compound of the Formula '1 above may be prepared by variousdifferent methods which involve well known chemical reaction principles.However, the following methods have been found to be particularlyconvenient and efiicient:

' Method A Reduction of a ketone of the formula wherein R and R arehydrogen or protective groups which may readily be split off again byhydrolysis, hydrogenolysis or alcoholysis during or subsequent to thereduction, preferred such protective groups being acyl or benzyl; and Ris hydrogen or a protective group for the amino group which can readilybe split off again during or subsequent to the reduction, preferablybenzyl. The reduction of the ketone 'II is preferably carried out bycatalytic hydrogenation in the presence of platinum, pallidum or nickelas a catalyst, whereby not only the keto group is converted into ahydroxyl group, but protective groups removable by hydrogenolysis, suchas 3,406,237 Patented Oct. 15, 1968 benzyl, are also simultaneouslyremoved. In the event that R and/0r R are acyl, they remain unaffectedby the catalytic hydrogenation of the keto group and may subsequently beremoved by hydrolysis or alcoholysis in customary fashion.

The reduction of the keto group may also be effected by reaction of theketone II with an alkali metal borohydride, preferably sodiumborohydride.

The ketones 'II, which are used as starting materials in this method,may themselves be prepared by the following procedures:

(1) Reaction of a bromoketone of the formula (|f-CHz-Br OR; (III)wherein R is hydrogen or -a hydrogen-protective group,

such as methyl, benzyl or preferably acyl, with an amine of the formulaCH3 (IV) wherein R is hydrogen or an amino-protective group, such asbenzyl which is preferred, and R is hydrogen or a hydroxy-protectivegroups, such as acyl, methyl or benzyl, and removal of the hydroxyandamino-protective groups, if necessary.

(2) Reductive alkylation of an amine of the formula H3 (V) wherein R hasthe same meanings as in Formula IV above, with a keto-aldehyde of theformula wherein R, has the same meanings as in Formula III above, andremoval of the 'aminoand hydroxy-protective groups, if necessary.

(3) Formation of the Schifts base from the amine V and the keto-aldehydeVI, and subsequent hydrogenation while maintaining the ketone group, thehydrogenation being preferably performed catalytically, and removal ofthe aminoand hydroxy-protective groups if necessary.

The sequence of the removal of the amino-protective group R thehydroxy-protective group R and/or R and the reduction of the ketonegroup may be varied, depending upon the procedures for removal of theprotective groups. If it is necessary for the removal of one or theother protective group to treat the intermediate compound with ahydrohalic acid, for instance, with hydrobromic acid in the case of theremoval of the methyl group in the R and/or R position, this removal isadvantageously performed prior to the reduction of the ketone group.

Method B Reductive alkylation of a compound of the formula I |JHCHz-NH2t 0H 0R2 3 wherein R has the same meanings as defined in Formula II,with a ketone of the formula wherein R has the same meanings as theFormula II.

The customary hydrogenation catalysts, such as palladium, platinum ornickel, may be used as catalysts for the reductive alkylation. Theprotective groups "R and R may be removed simultaneously during thereductive alkylation or also subsequent thereto. The aminoalcohols VIImay, for example, be obtained from the corresponding bromo-ketones byreaction with sodium phthalimide, saponification and reduction of theketone.

Method C Formation of the Sc'hitfs base from the amine VII and theketone VIII, and subsequent hydrogenation, which is advantageouslyperformed catalytically.

The compound of the Formula I above contains two asymmetric carbon atomsand therefore occurs in two stereoisorneric forms A and B, which may beseparated from each other by customary methods. Each of thesestereoisomers, in turn, occurs in the form of d,l-racemates which mayagain be separated into their optically active dand l-isomers by knownmethods.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely.

(VIII) Example 1.Preparation of l-p-hydroxyphenyl-Z-(B-3',5'-

dihydroxyphenyl p hydroxy)-ethylamino-propane by Method A (a)1-p-hydroxyphenyl-2-(;3-3,5' dihydroxy phenylp-oxo)ethylamino-propanehydrobromide.441 gm. (1.4 mols) of 3,S-acetoxy-a-bromo-acetophenone(M.P. 66 0.), prepared by bromination of 3,5-diacetoxy-acetophenone,were added to a solution of 714 gm. (2.8 mols) ofl-p-methoxyphenyl-2-benzylamino-propane in 1000 cc. of benzene, and theresulting solution mixture was refluxed for one hour. The molar excessof l-p-methoxyphenyl-2-benzylamino-propane precipitated out as itsbydrobromide. After separation of the precipitated hydrobromide of theamino component, the hydrochloride of1-p-methoxyphenyl-2-(fi-3',5'-diacetoxyphenyl [3 x0)-ethyl-benzylamino-propane was precipitated from the reaction solution byaddition of an ethanolic solution of hydrochloric acid. The precipitatewas separated and, without further purification, was de-acetylated byboiling it in a mixture of 2 liters of aqueous hydrochloric acid and 1.5liters of methanol. The resulting solution was filtered through :animalcharcoal and, after addition of 2 liters of methanol, it wasde-benzylated by hydrogenation at 60 C. over palladized. charcoal as acatalyst. After removal of the catalyst by filtration, the filtrate wasconcentrated by evaporation, whereupon the hydrochloride of1-p-methoxyphenyl-2-( B-3',5-dihydroxyphenyl-fl-oxo)-ethylamino-propane(M.P. 244 C.) crystallized out. For the purpose of demethylation, the350 gm. of the hydrochloride thus produced were refluxed for two hourswith 3.5 liters of aqueous 48% hydrobromic acid. Upon cooling of thereaction solution, 320 gm. of 1-p-hydroxyphenyl-2-(fi 3',5'dihydroxyphenyl-fi-oxo)- ethylamino-propane hydrobromide (M.P. 220 C.)crystallized out. (b) 100 gm. of the l-p-hydroxyphenyl-Z-(13-3,5-dihydroxyphenyl-B-oxo) ethylamino propane hydrobromide obtainedin the previous step were dissolved in hot water, and the aminoketonewas isolated as the difiiculty soluble sulfate by addition of an aqueouspotassium sulfate solution. For the purpose of hydrogenating the ketogroup, gm. of l-p-hydroxyphenyl- 2-(5-3',5'-dihydroxyphenyl-fl-oxo)ethylamino propane sulfate were dissolved in a mixture of 100 cc. ofmethanol and 100 cc. of water. After addition of a small amount ofhydrochloric acid, palladium chloride and activated charcoal, themixture was hydrogenated at 5070 C. and at 5 atmospheres gauge. Afterremoval of the catalyst by vacuum filtration, the filtrate wasevaporated to dryness in vacuo, whereby l-p-hydroxyphenyl-Z-(B-3,5'-dihydroxyphenyl-B-hydroxy)-ethylamino-propane sulfate was obtained. Thefree base of the formula OH on r p 0H was obtained from the sulfate byaddition of an aqueous sodium bicarbonate solution and shaking of themixture with ethylacetate. The hydrochloride of this compound (M.P.l82183 C.) was obtained by adding an ethereal solution of hydrochloricacid to the free base.

Example 2.Preparation of l-p-hydroxyphenyl-2-(fl-3,5-dihydroxy-phenyl-fl-hydroxy)-ethylamino-propane hydrobromide by Method A220 gm. of1-p-hydroxyphenyl-2-(B-3,5'-dihydroxyphenyl-B-oxo)-ethylamino-propanehydrobromide were dissolved in 1 liter of methanol, the resultingsolution was boiled with activated charcoal, the charcoal was filteredotf and the filtrate was hydrogenated in the presence of Raney nickel at60 C. and 5 atmospheres gauge. Thereafter, the catalyst was filteredotf, the methanolic solution was admixed with a small amount ofconcentrated hydrobromic acid, and the mixture was evaporated to drynessin vacuo. The residue was stirred with acetone, the mixture was vacuumfiltered and the filter cake was recrystallized from a mixture ofmethanol and ether. The l-p-hydroxyphenyl-Z-(5-3',5'-dihydroxyphenyl-B-hydroxy)-ethylaminopropane hydrobromide thus obtained had a meltingpoint of 222-223 C.

Analysis-Calculated: Br, 20.79%; N, 3.65%. Found: Br, 20.85%; N, 3.66%

Example 3.-Preparation of l-p-hydroxyphenyl-Z-(B-3',5'-

dihydroxyphenyl-fl-hydroxy)ethylamino propane and its hydrochloride byMethod B A mixture of 8.45 gm. (0.05 mol) ofl-(3,5'-di-hydroxyphenyl)-1-hydroxy-2-amino-ethane and 9 gm. (0.06 mol)of p-hydroxyphenyl acetone was added to cc. of methanol, 3 gm. ofglacial acetic acid were added thereto, and the resulting mixture washydrogenated in the presence of platinum under normal conditions. Afterthe absorption of hydrogen was complete, the catalyst was removed byvacuum filtration, an aqueous sodium bicarbonate solution was added tothe filtrate and the l-p-hydroxypheny1-2-(B-3,5'-dihydroxyphenyl Bhydroxy)- ethylamino-propane formed thereby was taken up in ethylacetate. The addition of an ethereal solution of hydrochloric acid tothis ethyl acetate solution led to the precipitation of thehydrochloride of the base, which crystallized upon treatment with amixture of acetonitrile and ether (M.P. 183 C.).

Example 4.--Separation of the hydrobromide of l-p-hydroxyphenyl-2-(3-315 -dihydroxyphenyl fl hydroxy)- ethylamino-propane into itsstereoisomeric components 360 gm. of thel-p-hydroxyphenyl-2-(p-3',5'-dihydroxyphenyl-fl-hydroxy)-ethylaminopropane hydrobromide obtained in Example 2 were recrystallized severaltimes from glacial acetic acid. gm. of the stereoisomeric form A of thehydrobromide were obtained, which had a melting point of 224.5--226 C.

The stereoisomeric form B of the hydrobromide, which had a melting pointof 188-190 C., was obtained by treating the concentrated mother liquorsof the glacial acetic acid recrystallization step with acetonitrile.

The compounds according to the present invention, that is, the racemic,optically active and stereoisomeric forms of the diaralkylamine of theFormula I and the nontoxic, pharmacologically acceptable acid additionsalts of any of these forms, have useful pharmacodynamic properties.More particularly, they exhibit bronchospasmolytic activities inwarm-blooded animals, such as guinea pigs, and are characterized bygreat stability, especially against oxidative action. Hence, they areadministrable to warm-blooded animals perorally as well as parenterally,including by inhalation. Further, they are rapidly and readily absorbedfrom the gastro-intestinal tract of warm-blooded animals, and maintain along duration of effective action. Their side effects upon the heart andthe blood pressure are very weak, which is particularly noteworthybecause known compounds of similar structure produce an undesirablesignificant side effect upon the heart rate and the blood pressure. Morespecifically, the compounds of the the present invention producepositive inotropic and positive chronotropic elTects on the heart anddistinct, although slight, hypotension.

Typical examples of pharmacologically acceptable, non-toxic acidaddition salts are their hydrochlorides, hydrobromides, sulfates,phosphates, nitrates, acetates, propionates, butyrates, valerates,oxalates, malonates, succinates, maleates, fumarates, lactates,tartrates, citrates, malates, benzoates, phthalates, cinnamates,salicylates, nicotinates, furoates, 8-chlorotheophyllinates, and thelike. The hydrobromides and hydrochlorides, however, are preferred.

For pharmaceutical purposes the compounds of the invention areadministered perorally or parenterally as active ingredients incustomary dosage unit compositions, that is, compositions in dosage unitform consisting essentially of an inert pharmaceutical carrier and onedosage unit of the active ingredient, such as tablets, hypodermicsolutions, inhalation solutions, aerosols, and the like.

The individual dosage unit ranges of the compounds ac cording to thepresent invention are 0.008-0.5 mgm./kg. bodyweight perorally and0.00080.09 mgm./kg. bodyweight subcutaneously or intramuscularly, andtheir concentration in inhalation solutions may range from 0.1 to

. 10% by weight, based on the total weight of the solution.

For instance, the average broncho-spasmolytically effective singledosage range of the stereoisomeric form A ofd,l-1-p-hydroxypheuyl2-(fl-3,5-dihydroxyphenylphydroxy)-ethyl-aminopropane is 0008-009 mgrn./ kg. perorally; foradministration by the subcutaneous or intramuscular route the averageeffective single dosage range of the same compound is 00008-002-mgm./kg. The effective concentration range of the compound in aninhalation solution is from 0.1 to 2% by weight.

The following examples illustrate various dosage unit compositionscomprising a compound of the present invention as the activebroncho-spasmolytic ingredient. The parts are parts by weight unlessotherwise specified.

Example 5 Inhalation aerosol.The aerosol composition was compounded incustomary fashion from the following ingreclients:

Parts Stereoisomeric Form A of d,l-1-p-hydroxyphenyl-2-(13-3,5-dihydroxyphenyl-fi-hydroxy)-ethylamino-propane hydrobromide0.15 Soybean-lecithin 0.05

Propellent gas mixture (Frigen 11, 12 and 114), q.s.

ad 100.00 parts.

A two-second burst of this aerosol from a pressurized aerosol can, whenadministered through the respiratory tract to warm-blooded animals ofabout 60 kg. body weight suffering from broncho-spasms, produced verygood broncho-spasmolytic elfects.

6 Example 6 Inhalation solution.--The solution was compounded from thefollowing ingredients:

Parts Stereoisomeric Form A of d,l-1-p-hydroxyphenyl-2-(pi-3,5'-dihydroxyphenyl-B-hydroxy)-ethyl amino-propane hydrobromide1.00 Sodium pyrosulfite 0.05 Disodium salt of E.D.T.A. 0.05

Distilled water, q.s. ad 100.00 parts.

The solution was dispensed through a metered inhalation vaporizer havinga spray output capacity of 12.5 liters per minute. When administered bythe respiratory route to warm-blooded animals of about kg. body weightrequiring broncho-spasmolytic treatment, 1 to 2 metered bursts producedvery good broncho-spasmolytic effects.

Example 7 Tablets-The tablet composition was compounded from thefollowing ingredients:

The individual ingredients were homogeneously admixed, and thecomposition was pressed into 200 mgm.-tablets. Each tablet contained 5mgm. of the ethylamino-propane compound and, when administered by theoral route to warm-blooded animals of about 60 kg. body weight requiringbroncho-spasmolytic treatment, produced very good broncho-spasmolyticefiects.

Example 8 Hypodermic solution-The solution was compounded from thefollowing ingredients:

Parts Stereoisomeric Form A of d,l-1-p-hydroxyphenyl- 2 (,3 3',5'dihydroxyphenyl 13 hydroxy)- ethylamino-propane hydrobromide 0.250Sodium pyrosulfite 0.100 Disodium salt of E.D.T.A 0.500 Sodium chloride8.500

Double-distilled water, q.s. ad 1000.000 by volume.

The solution was filled into 1 cc.-ampules, which were then sterilizedand sealed. Each ampule contained .25 mgrn. of the active ingredient.When administered by the parenteral route to warm-blooded animals ofabout 60 kg. body weight requiring broncho-spasmolytic treatment, thecontents of the ampule produced very good bronchospasmolytic eifects.

While the preceding dosage unit composition examples illustrate only onenon-toxic acid addition salt of a stereoisomer of the compound of thepresent invention as an active ingredient, it should be understood thatany of the other forms of the compound embraced by Formula I or anon-toxic, pharmacologically acceptable acid addition salt thereof maybe substituted for the single illustrated compound in Examples 5 through8. Also, the illustrated active ingredient content in these examples maybe varied to achieve the above-indicated dosage unit range to meetparticular requirements.

Although the present invention has been illustrated with the aid ofcertain specific embodiments, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

-1. A broncho-spasmolytic composition in dosage unit form consistingessentially of an inert pharmaceutical carrier and a broncho-spasmolyticamount of a racemic mixture of 1p-hydroxyphenyl-Z-(B-S",5-dihydroxyphenyl-flhydroxy)-ethyla"mino-propane,an optical antipode thereof, a stereoisomer thereof, or a non-toxic,pharmacologically acceptable acid addition salt of said racemic mixture,optical antipode or stereoisomer.

2. A broncho-spasmolytic aerosol composition consisting essentially ofan aerosol container, an aerosol propellant and from 0.1 to 10% byweight, based on the total weight of said composition, of a racemicmixture of 1 p hydroxyphenyl 2 (B 3',5'dihydroxyphenylfl-hydroxy)-ethylamino propane, an optical antipodethereof, a stereoisomer thereof, or a non-toxic, pharmacologicallyacceptable acid addition salt of said racemic mixture, optical antipodeor stereoisomer.

3. The method of relieving broncho-spasms in warmblooded animals, whichcomprises administering to said animals an efiective broncho-spasmolyticdose of a racemic mixture of l p-hydroxyphenyl-2-(fi-3,5'-dihydroxyphenyl-fl-hydroxy)-ethylamino-propane, an optical antipode thereof, astereoisomer thereof, or a non-toxic, pharmacologically acceptable acidaddition salt of said racemic mixture, optical antipode or stereoisomer.

References Cited UNITED STATES PATENTS 3,135,797 6/1964 Biel 260-5706FOREIGN PATENTS 542,265 4/ 1956 Belgium. 623,286 7/ 1961 Canada. 789,033l/ 1958 Great Britain.

. OTHER REFERENCES Moed et al., Rec. Trav. Chim., vol. 74, pp. 921-24(1955).

ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner.

